International Journal of Molecular Sciences Review Niacin in the Central Nervous System: An Update of Biological Aspects and Clinical Applications Valeria Gasperi *,†, Matteo Sibilano †, Isabella Savini and Maria Valeria Catani * Department of Experimental Medicine, Tor Vergata University of Rome, Via Montpellier 1, 00133 Rome, Italy; [email protected] (M.S.); [email protected] (I.S.) * Correspondence: [email protected] (V.G.); [email protected] (M.V.C.); Tel.: +39-06-72596465 (V.G. & M.V.C.) † These authors contributed equally to this work. Received: 30 January 2019; Accepted: 20 February 2019; Published: 23 February 2019 Abstract: Niacin (also known as “vitamin B3” or “vitamin PP”) includes two vitamers (nicotinic acid and nicotinamide) giving rise to the coenzymatic forms nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). The two coenzymes are required for oxidative reactions crucial for energy production, but they are also substrates for enzymes involved in non-redox signaling pathways, thus regulating biological functions, including gene expression, cell cycle progression, DNA repair and cell death. In the central nervous system, vitamin B3 has long been recognized as a key mediator of neuronal development and survival. Here, we will overview available literature data on the neuroprotective role of niacin and its derivatives, especially focusing especially on its involvement in neurodegenerative diseases (Alzheimer’s, Parkinson’s, and Huntington’s diseases), as well as in other neuropathological conditions (ischemic and traumatic injuries, headache and psychiatric disorders). Keywords: central nervous system; diet; NAD(P); neurodegenerative diseases; niacin; nicotinamide; nicotinic acid; vitamin B3 1. Introduction Niacin (also known as “vitamin B3” or “vitamin PP”) is the generic descriptor for two vitamers, nicotinic acid (pyridine-3-carboxylic acid) and nicotinamide (nicotinic acid amide), that give rise to the biologically active coenzymes, nicotinamide adenine dinucleotide (NAD) and its phosphate analog, the nicotinamide adenine dinucleotide phosphate (NADP) [1] (Figure1). The two coenzymes take part in redox reactions crucial for energy production: in particular, the pyridinic ring can accept and donate a hydride ion (:H−, the equivalent of a proton and two electrons), thus acting as an electron carrier. Nonetheless, NAD and NADP play different metabolic roles in the cytosol: the NADH/NAD+ ratio is small (about 8 × 10−4), thus favoring oxidative catabolism, whereas the NADPH/NADP+ ratio is higher (about 75), thus providing a strongly reducing environment for biosynthetic reactions [2,3]. Maintenance of the intracellular NAD pool is not only important to fuel redox metabolism, but also to support NAD-dependent, non-redox signaling pathways. NAD is indeed a substrate of ADP-ribosyltransferases that catalyze ADP-ribose transfer reactions, thus breaking down NAD to nicotinamide and ADP-ribosyl products, which play a key role in cellular signaling cascades regulating gene expression, cell cycle progression, insulin secretion, DNA repair, apoptosis and aging [4–6]. Finally, NAD has also been recognized as an endogenous agonist of purinergic P2Y1 and P2Y11 membrane subtype receptors, through which it inhibits neurotransmission in visceral smooth muscles [7] and activates immune cells [8,9], respectively. Int. J. Mol. Sci. 2019, 20, 974; doi:10.3390/ijms20040974 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2019, 20, 974 2 of 26 Int. J. Mol. Sci. 2019, 20, x FOR PEER REVIEW 2 of 27 FigureFigure 1. 1.Chemical Chemical structuresstructures of niacin niacin vitamers vitamers (A ()A and) and active active coenzymatic coenzymatic forms forms (B). NAD: (B). NAD: nicotinamidenicotinamide adenin adenin dinucleotide. dinucleotide. NADP: nicotinamide nicotinamide adenin adenin dinucleotide dinucleotide phosphate. phosphate. 2. NiacinMaintenance Sources of the intracellular NAD pool is not only important to fuel redox metabolism, but also to support NAD-dependent, non-redox signaling pathways. NAD is indeed a substrate of ADP- ribosyltransferasesHumans obtain niacinthat catalyze from bothADP-ribose endogenous transfer and reactions, exogenous thus sources.breaking down Only 2%NAD of to dietary tryptophannicotinamide (Trp) and is convertedADP-ribosyl into products, niacin viawhich a multistep play a key pathway role in (seecellular in next signaling sections), cascades occurring mainlyregulating in the gene liver expression, [10]. Diet cell provides cycle progression, the vitamin insulin as nicotinic secretion, acid, DNA nicotinamide repair, apoptosis and and Trp, aging as well as the active[4–6]. Finally, coenzymatic NAD has forms also been of niacin. recognized as an endogenous agonist of purinergic P2Y1 and P2Y11 membrane subtype receptors, through which it inhibits neurotransmission in visceral smooth 2.1.muscles Exogenous [7] and Sources activates immune cells [8,9], respectively. 2.Niacin Niacin is Sources found in animal and vegetable foods. In meat and fish, the vitamin is present as NAD(P), whose amounts are higher in unprepared foods compared to processed foods (enzymatic hydrolysis of Humans obtain niacin from both endogenous and exogenous sources. Only 2% of dietary the coenzymes can occur during food preparation). tryptophan (Trp) is converted into niacin via a multistep pathway (see in next sections), occurring In mature cereal grains (particularly in corn), niacin is largely present as niacin-glycoside and, in mainly in the liver [10]. Diet provides the vitamin as nicotinic acid, nicotinamide and Trp, as well as a minorthe active proportion, coenzymatic peptide-bound forms of niacin. niacin, compounds collectively termed “niacinogens” [11]. When complexed in niacinogens, niacin is poorly available (only ~ 30%), as intestinal enzymes are not able to free2.1. niacin; Exogenous nonetheless, Sources alkali treatment of the grain increases niacin bioavailability [11]. OnceNiacin ingested, is found free in niacin animal can and be adsorbedvegetable foods. in the stomach,In meat and although fish, the the vitamin small intestineis present absorbs as it faster.NAD(P), The mechanism whose amounts of transport are higher across in unprepared the enterocyte foods brushcompared border to processed membrane foods is not (enzymatic fully clarified yet.hydrolysis Several transporters, of the coenzymes indeed, can occur appear during to befood involved preparation). in intestinal niacin uptake; among them, the mostIn common mature cereal are thegrains human (particularly organic in anioncorn), niacin transporter-10 is largely present (hOAT-10, as niacin-glycoside a proton-driven and, carrier thatin also a minor mediates proportion, the transport peptide-bound of urate niacin, and p compounds-aminohippurate) collectively [12 ],termed responsible “niacinogens” for niacin [11]. uptake at physiologicalWhen complexed concentrations in niacinogens, [13 niacin], and is the poorly sodium-coupled available (only monocarboxylate ~ 30%), as intestinal transporter enzymes are (SMCT1 or SLC5A8,not able to a transporterfree niacin; nonetheless, for lactate, alkali pyruvate treatment and of short-chain the grain increases fatty acids), niacin specifically bioavailability active [11]. at high Once ingested, free niacin can be adsorbed in the stomach, although the small intestine absorbs pharmacological doses of nicotinic acid [14,15]. it faster. The mechanism of transport across the enterocyte brush border membrane is not fully NAD and NADP are quickly hydrolyzed, by intestinal mucosa and liver glycohydrolases, clarified yet. Several transporters, indeed, appear to be involved in intestinal niacin uptake; among to nicotinamidethem, the most that common is subsequently are the human transported organic an toion tissues, transporter-10 where it (hOAT-10, is converted a proton-driven into coenzymatic formscarrier as necessary. that also mediates It seems the noteworthy transport of that urate nicotinamide and p-aminohippurate) moves freely [12], into responsible or out of for the niacin brain [16] and,uptake as discussed at physiological in the next concentrations sections, such [13], a an propertyd the sodium-coupled has important monocarboxylate neurobiological transporter implications. (SMCT1 or SLC5A8, a transporter for lactate, pyruvate and short-chain fatty acids), specifically active 2.2.at Endogenous high pharmacological Synthesis doses of nicotinic acid [14,15]. Starting from dietary Trp, niacin is synthesized via the kynurenine pathway (KP) (Figure2), occurring mainly in the liver and, to a lesser extent, in extrahepatic tissues (especially upon immune cell activation) [17–19]. Int. J. Mol. Sci. 2019, 20, x FOR PEER REVIEW 3 of 27 NAD and NADP are quickly hydrolyzed, by intestinal mucosa and liver glycohydrolases, to nicotinamide that is subsequently transported to tissues, where it is converted into coenzymatic forms as necessary. It seems noteworthy that nicotinamide moves freely into or out of the brain [16] and, as discussed in the next sections, such a property has important neurobiological implications. 2.2. Endogenous Synthesis Starting from dietary Trp, niacin is synthesized via the kynurenine pathway (KP) (Figure 2), occurring mainly in the liver and, to a lesser extent, in extrahepatic tissues (especially upon immune Int. J. Mol. Sci. 2019, 20, 974 3 of 26 cell activation) [17–19]. Figure 2. De novo synthesis of NAD(P) from tryptophan, nicotinamide and nicotinic acid. (1)